TY - JOUR
T1 - The effect of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and charybdotoxin (CTX) on relaxations of isolated cerebral arteries to nitric oxide
AU - Onoue, Hisashi
AU - Katusic, Zvonimir S.
N1 - Funding Information:
This work was supported in part by National Heart, Lung, and Blood Institute grant HL-53524, and the Mayo Foundation. Dr. Onoue was supported by a scholarship from Uehara Memorial Foundation (Tokyo, Japan). The authors would like to thank Janet Beckman for preparing the manuscript.
PY - 1998/2/23
Y1 - 1998/2/23
N2 - The mechanism underlying smooth muscle relaxations of cerebral arteries in response to nitric oxide is still not completely understood. The present study was designed to determine the role of soluble guanylate cyclase in the relaxations to a nitric oxide/nucleophile complex, diethylaminodiazen-1-ium- 1,2-dioate (DEA-NONOate). Rings of canine middle cerebral arteries without endothelium were suspended in Krebs-Ringer bicarbonate solution for isometric tension recording. The levels of guanosine 3',5'-cyclic monophosphate (cyclic GMP) were measured by radioimmunoassay technique. During contractions to uridine 5'-triphosphate (UTP), DEA-NONOate (10-10 to 10-5 M) caused concentration-dependent relaxations. Measurements of cyclic GMP levels in cerebral arterial wall demonstrated that DEA-NONOate is a potent stimulator of guanylate cyclase and subsequent formation of cyclic GMP. Increasing concentrations of a selective soluble guanylate cyclase inhibitor, 1H- [1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), caused concentration- dependent reduction of both cyclic GMP production and relaxations to DEA- NONOate. Interestingly, in the presence of the highest concentration (3 x 10-6 M) of ODQ, production of cyclic GMP in response to 10-6 M of DEA- NONOate was abolished, whereas the same concentration of DEA-NONOate caused almost complete relaxation, suggesting that mechanisms independent of cyclic GMP production may mediate relaxing effect of high concentration of a nitric oxide donor. A selective Ca2+-activated potassium channel blocker charybdotoxin (CTX) significantly reduced relaxations to DEA-NONOate resistant to ODQ, supporting the idea that in cerebral arteries nitric oxide may activate potassium channels independently of cyclic GMP. The results of our study suggest that under physiological conditions, guanylate cyclase is a key mediator of cerebral arterial relaxations to nitric oxide. However, under pathological conditions associated with induction of nitric oxide synthase and increased biosynthesis of nitric oxide (e.g., cerebral ischemia, inflammation, sepsis), mechanisms other than formation of cyclic GMP may be activated.
AB - The mechanism underlying smooth muscle relaxations of cerebral arteries in response to nitric oxide is still not completely understood. The present study was designed to determine the role of soluble guanylate cyclase in the relaxations to a nitric oxide/nucleophile complex, diethylaminodiazen-1-ium- 1,2-dioate (DEA-NONOate). Rings of canine middle cerebral arteries without endothelium were suspended in Krebs-Ringer bicarbonate solution for isometric tension recording. The levels of guanosine 3',5'-cyclic monophosphate (cyclic GMP) were measured by radioimmunoassay technique. During contractions to uridine 5'-triphosphate (UTP), DEA-NONOate (10-10 to 10-5 M) caused concentration-dependent relaxations. Measurements of cyclic GMP levels in cerebral arterial wall demonstrated that DEA-NONOate is a potent stimulator of guanylate cyclase and subsequent formation of cyclic GMP. Increasing concentrations of a selective soluble guanylate cyclase inhibitor, 1H- [1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), caused concentration- dependent reduction of both cyclic GMP production and relaxations to DEA- NONOate. Interestingly, in the presence of the highest concentration (3 x 10-6 M) of ODQ, production of cyclic GMP in response to 10-6 M of DEA- NONOate was abolished, whereas the same concentration of DEA-NONOate caused almost complete relaxation, suggesting that mechanisms independent of cyclic GMP production may mediate relaxing effect of high concentration of a nitric oxide donor. A selective Ca2+-activated potassium channel blocker charybdotoxin (CTX) significantly reduced relaxations to DEA-NONOate resistant to ODQ, supporting the idea that in cerebral arteries nitric oxide may activate potassium channels independently of cyclic GMP. The results of our study suggest that under physiological conditions, guanylate cyclase is a key mediator of cerebral arterial relaxations to nitric oxide. However, under pathological conditions associated with induction of nitric oxide synthase and increased biosynthesis of nitric oxide (e.g., cerebral ischemia, inflammation, sepsis), mechanisms other than formation of cyclic GMP may be activated.
KW - Cerebral artery
KW - Cyclic GMP
KW - Guanylate cyclase
KW - Nitric oxide
KW - Potassium channel
KW - Vasodilatation
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U2 - 10.1016/S0006-8993(97)01393-0
DO - 10.1016/S0006-8993(97)01393-0
M3 - Article
C2 - 9526059
AN - SCOPUS:0032559655
SN - 0006-8993
VL - 785
SP - 107
EP - 113
JO - Brain Research
JF - Brain Research
IS - 1
ER -